Management and Outcomes of Anti-thrombotic Medication Use in Thrombocytopenia

* Thrombocyte-level cohorts Patients will be divided into two groups based on the platelet level at study index .

1. Thrombocytopenic Cohort: Patients with morning platelet count below 50*109/L at study index. This is the main study cohort for all analyses
2. Non-thrombocytopenic Cohort: Patients whose morning platelet count is ≥ 50*109/L at study index will be considered as a reference group, and not included in the primary analysis.
* Analysis of outcomes:

By definition, there will be an intervention at the time of study index (baseline), meaning that even if no change is made, it will be considered an intervention. Each patient may have multiple exposures/interventions over the study.

Therefore, in a time dependent analysis, each outcome will be linked to the exposure/intervention at study index.

Each exposure/intervention will be linked with the platelet level on the day of the intervention.

#Competing Events:

The following events (in addition to death) will be considered competing events and will be considered as such in the statistical analyses of the outcomes:

1. The composite primary outcome
2. change in the antithrombotic regimen after study index
3. diagnosis of HIT or TTP
4. a change in the hematological malignancy treatment regimen. Study follow-up will continue after these events, and study data will continue to be recorded until censorship for end of study period or death.

* Detecting selection bias:

Patients fulfilling the inclusion criteria but not included in the study, will be detected by reviewing the medical records of the hematology institute, weekly. The baseline characteristics and reason for not including these patients will be recorded retrospectively in the "not-included cohort". The baseline characteristics of this cohort will be compared with the study cohort to ascertain whether selection bias exists.

• Hold (Drug): Hold antithrombotic therapy
• Prophylactic dose antithrombotic (Drug): Reduction in antithrombotic medication dose to prophylactic dose (without changing type)
• Change antithrombotic Drug (Drug): Change in type of antithrombotic therapy
• Change platelet transfusion threshold (Biological): Increase or reduce platelet transfusion threshold
• Full dose antithrombotics (Drug): Continue full dose antithrombotic therapy
• Mechanical measures (Device): Mechanical measures to reduce thrombotic risk including: IVC filter insertion, Intermittent Pneumatic Compression (IPC), Removal of Central venous catheter
• Intermediate dose antithrombotic (Drug): Reduction in antithrombotic medication dose to prophylactic dose (without changing type). Intermediate dose in between prophylactic and full dose

Primary outcomes

• Composite of major bleeding or thrombosis [30 days (from study index) or until death (whichever first)]: 1\) ISTH-defined Major bleeding events defined as: Fatal bleeding; bleeding into a critical organ; clinically overt bleeding associated with a decrease in hemoglobin level of more than 2 g/dL or leading to the transfusion of two or more units of blood OR: 2) Thrombosis defined as: Any symptomatic deep or superficial venous or arterial thromboembolism demonstrated on objective imaging/laboratory tests. Ischemic strokes with no immediate imaging signs will also be considered events, provided this was diagnosed by a neurologist and that the patient had objective neurological signs.

Secondary outcomes

• Platelet transfusion related adverse effects [30 days (from study index) or until death (whichever first)]: Number of adverse effects (all types and individually grouped) related to platelet/plasma transfusion, occurring within 24 hours of transfusion
• Clinically Relevant non-Major Bleeding [30 days (from study index) or until death (whichever first)]: Defined according to the ISTH criteria published in the journal of thrombosis and Hemostasis by Kaatz et al in 2015
• Number of platelet tranfusions [30 days (from study index) or until death (whichever first)]: Number of platelet transfusions
• Number of RBC tranfusions [30 days (from study index) or until death (whichever first)]: Number of red blood cell transfusions
• Death [30 days (from study index)]: death from any cause
• Change in antithrombotic management [30 days (from study index) or until death (whichever first)]: Change in dose/type of antiplatelet or anticoagulant medication OR change in platelet threshold, AFTER the initial intervention which was recorded at study index.

Other outcomes

• peak anticoagulant intensity [3 days after study index]: anti-Xa, Hemoclot, INR, aPTT will be measured at peak, depending on the anticoagulant drug. Patients will be classified as having sub-therapeutic, therapeutic, supra-therapeutic treatment levels, based upon the reference range at the central laboratory. Only relevant for patients with anticoagulation undergoing dose change.
• Whole blood coagulation [3 days after study index]: Measured by rotational thromboelastometry (ROTEM) drawn at study index

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Any hematological malignancy with or without active treatment (including autologous or allogeneic stem cell transplantation), irrespective of the treatment line and disease status.
* Disease-related and/or current/predicted treatment-related thrombocytopenia (<50 X 109/L) of any duration.
* Current antiplatelet and/or anticoagulant treatment of any duration and for any indication. This treatment may have been started before or after diagnosis of the hematological malignancy and thrombocytopenia.

"Current" refers to the time when the current thrombocytopenia, or risk thereof (i.e. "predicted"), was first identified (even if the treatment is subsequently stopped)

Exclusion Criteria:

* Previous thrombocytopenia (<50 X 109/L) while using the current antithrombotic regimen.
* Current diagnosis of heparin induced thrombocytopenia (HIT) or thrombotic thrombocytopenia purpura (TTP)

• Avi Leader, MD, Principal investigator, Rabin Medical Center, Petah Tikva, Israel
• Hugo ten Cate, MD, PhD, Study chair, Maastricht University Medical Center, Maastricht
• Anna Falanga, MD, Study chair, A.O. Papa Giovanni XXIII - S.I.M.T.